The idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of diffuse parenchymal diseases of unknown etiology. The pathologic classification of the IIPs has evolved considerably over the past 50 years and is based on the histopathologic pattern. A final, and clinically relevant, diagnosis often depends on integration of the histologic findings with the radiologic and clinical presentations. Specimens for histopathologic evaluation are best obtained by surgical wedge biopsy to allow the accurate recognition of the involvement patterns of these disorders. Two of the most common IIPs, idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP), differ with respect to prognosis. Patients with IPF have a poorer prognosis than those with NSIP and most other IIPs. Within the NSIP diagnosis, a fibrotic pattern seems to be associated with a worse outcome than a cellular pattern. By distinguishing IPF from other clinicopathologic entities, clinicians should be better able to identify optimal treatment strategies and hopefully to improve patient outcomes.

Figures in this Article

The idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of diffuse parenchymal diseases of unknown etiology, which are characterized by varying patterns of inflammation and fibrosis of the lung parenchyma.1In older adult patients, idiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing alveolitis, is the most common of the IIPs but is, nevertheless, a rare disorder. IPF typically presents in persons aged 40 to 70 years and occurs somewhat more frequently in men.2The prevalence of IPF has been reported to increase with age, ranging from 2.7 per 100,000 persons among those aged 35 to 44 years to > 175 per 100,000 persons among those > 75 years of age.3 The median survival time is about 3 years from the time of diagnosis.1,4–6

According to the 2000 American Thoracic Society (ATS) and European Respiratory Society (ERS) consensus statement,2 a definitive diagnosis of IPF requires a histologic pattern of usual interstitial pneumonia (UIP) found on a surgical lung biopsy specimen. A confident diagnosis of IPF can be made in the absence of a surgical lung biopsy specimen if the following four major criteria and three of the four minor criteria are met.2

In cases with atypical clinical or radiologic features, a surgical lung biopsy is necessary to obtain an accurate diagnosis.2 Ultimately, the diagnosis of IPF is a dynamic process requiring close collaboration among the pulmonologist, radiologist, and pathologist. The final diagnosis should be rendered after each specialist has reviewed all available clinical and histologic information.

At the turn of the 20th century, it was recognized that some patients died with bilateral lung disease that was unrelated to the common nontraumatic causes of death at that time (ie, infection and malignant tumor). At autopsy, the lungs had the appearance of a cirrhotic liver, shrunken, scarred, cystic, and replete with smooth muscle (ie, muscular cirrhosis of the lung). This cystic and scarring process preferentially involved the peripheral aspects of the lungs, especially the bases, with relative sparing of more central areas and the apices. The presence of these cystic structures engendered the use of the term honeycomb lung or simply honeycomb change.

In 1944, Hamman and Rich7 described a group of four otherwise healthy patients who developed rapid and fulminantly progressive lung disease, and died of respiratory failure within 1 to 3 months of presentation. At autopsy, these patients had advanced honeycomb changes and fibrosis in their lungs. The patients had no apparent commonalities. This disorder became known as Hamman-Rich syndrome.

The concept that interstitial fibrosis could develop very rapidly in the lung influenced Dr. Averill Liebow, a noted pulmonary pathologist. Aided by the increasing availability of lung biopsy specimens, in 1969 he published8–9 a classification scheme for cases of diffuse interstitial pneumonia unrelated to infection or malignancy that was based on specific histologic criteria. He termed the diseases idiopathic, because the cause was unknown, and divided them into the following five groups based primarily on distinctive histopathologic attributes: UIP; bronchiolitis obliterans with interstitial pneumonia (BIP); desquamative interstitial pneumonia (DIP); lymphoid interstitial pneumonia (LIP); and giant cell interstitial pneumonia (GIP). At about the same time, a more limited European classification was also being defined.

Liebow thought that the most common or usual type of diffuse lung fibrosis occurring in older individuals was UIP. The process was distinctive in that it produced fibrosis that began at the periphery of lobules and tended to spare more central parts. Each lobule appeared to be affected to different degrees. Some were destroyed, and others showed lesser fibrosis, frequently attended by aggregates of crescent-shaped fibroblastic foci that encroached on the lung tissue. The European classification included the same disorder, but termed it cryptogenic fibrosing alveolitis, because (1) it was viewed as a process of unknown etiology (cryptogenic), (2) it resulted in progressive active fibrosis (fibrosing), and (3) it seemed to be the result of an inflammatory disease at the level of the alveolus (alveolitis).

Liebow described BIP8–9 as a disease process characterized by some interstitial inflammation and prominent polypoid aggregates of immature fibroblasts occupying the alveolar spaces. The European classification included the same disease process, but referred to it as cryptogenic organizing pneumonia (COP) because (1) it was a process of unknown origin (cryptogenic), and (2) it showed a histopathologic appearance similar to organizing infectious pneumonia (organizing pneumonia).

Two additional idiopathic diseases in the Liebow classification were based on cellular infiltrates, either in the alveolar spaces (DIP) or in the alveolar walls (LIP). In DIP, the alveolar spaces were filled with pink cells that Liebow et al10thought were epithelial cells sloughed into the alveoli, and, thus, they used the term “desquamation.” It was subsequently determined by electron microscopy that these cells are actually macrophages. These macrophages contained delicate brown pigment, which is consistent with the relationship of this pathology to cigarette smoking (so-called smoker’s macrophages).11 LIP was characterized by a prominent accrual of lymphoid cells into the alveolar walls and relative sparing of alveolar spaces. The final element of the Liebow classification was GIP, a diffuse lung disease characterized by the accumulation of peculiar multinucleated giant cells in the vicinity of bronchioles, and associated with variable centrilobular fibrosis and inflammation. Interestingly, the European classification did not seem to have a corollary for these latter entities of the Liebow classification.

The classification system evolved over the years as entities were attributed to specific causation (ie, GIP and LIP) or were modified/renamed (ie, DIP and BIP). GIP was attributed to cobalt pneumoconiosis resulting from exposure to tungsten carbide fumes from hard metal processing. LIP was shown, in many of the original cases, to be a low-grade form of non-Hodgkin lymphoma, known as MALT lymphoma.1 Interestingly, a similar pattern of diffuse inflammatory lung disease became apparent in HIV-infected individuals and was referred to as “lymphocytic interstitial pneumonia,” unfortunately using the same acronym. DIP has almost disappeared from use in consultative practice. Most cases that would have been classified as DIP in Liebow’s day are now recognized as something else (eg, nonspecific interstitial pneumonia [NSIP] in a smoker), and the smoking-related disorder is referred to as respiratory bronchiolitis-associated interstitial lung disease (RB-ILD).,12DIP is now generally considered to represent the extreme manifestation of a spectrum that includes RB-ILD at the opposite end.13 BIP was subsequently renamed idiopathic bronchiolitis obliterans-organizing pneumonia, and, as seeming vindication of our European colleagues, the updated ATS/ERS classification (see below)1 of the IIPs concluded that COP is a more appropriate term for this condition.14–15 In the final analysis, UIP is the only histologic pattern that has stood the test of time from the original Liebow classification scheme, even though Liebow’s conceptualization of UIP was broader in scope than UIP in contemporary practice (eg, UIP from rheumatoid arthritis or UIP from asbestosis).

In 2002, a formal international consensus committee, under the auspices of the ATS/ERS, proposed an updated classification of the IIPs.1 The new consensus classification amalgamated distinct histologic patterns with clinical and radiologic findings.1 The consensus committee thought that sufficient differences existed among the clinicopathologic entities of IIP to consider them as separate disorders. These entities can be clinically categorized according to presentation as acute, subacute, and chronic diseases (Table 1
). Acute interstitial pneumonia (AIP) is a rapidly progressive disease of unknown etiology having a histologic pattern of diffuse alveolar damage, including a uniform temporal appearance, alveolar septal thickening due to organizing fibrosis, variable airspace organization, and hyaline membranes.,1 AIP is analogous to the acute disorder described by Hamman and Rich.7 On the other end of the spectrum, IPF is a chronic, smoldering disease of unknown etiology that progresses over the course of many months to years. Findings characteristic of IPF are described in the following section. The other clinicopathologic entities follow a subacute course and evolve over weeks to many months. All of these subacute diseases are characterized by ground-glass infiltrates on radiographic evaluation, but require histologic evaluation for differentiation. In clinical practice, the distinction of UIP from NSIP is perhaps the most important, and in some cases this can be challenging, especially in those NSIP patients in whom inflammation is accompanied by some degree of fibrosis.

As noted previously, the histopathologic pattern of UIP is essential for the clinical diagnosis of IPF.1–2 According to the ATS/ERS consensus statement,2 UIP is characterized by dense fibrosis that causes architectural destruction with frequent honeycombing, scattered fibroblast foci, and patchy lung involvement, usually with a pleural and paraseptal distribution.1 The disease is typically worse in the lower lobes. At low magnification, the lung characteristically has a heterogeneous appearance with alternating areas of normal parenchyma, fibrosis, and honeycomb cysts.1–2 Fibrotic areas contain dense acellular collagen, abundant smooth muscle proliferation, and discrete foci of proliferating fibroblasts, which are referred to as fibroblastic foci. These appear as crescent-shaped mounds when viewed in two-dimensional tissue sections, but a three-dimensional reconstruction suggests that they have a linear appearance, “wandering” over the periphery of the lobules. Over time, the fibrosis extends inward from the outside of the lobule toward the center, until the alveolar walls are replaced by dense fibrosis (Fig 1
). This process ultimately creates a cyst that is lined with terminal bronchiolar columnar cells, and contains mucous and inflammatory cells, typically lymphocytes and plasma cells. Possibly related to the pathogenesis of IPF is the consistent presence of hyperplastic type II pneumocytes, which are seen mainly in association with fibroblastic foci, suggesting a persistent basement membrane injury with frustrated cellular repair. In UIP, biopsy specimens should contain areas of relatively normal lung parenchyma.,1–2 However, acute lesions superimposed on the UIP histology may be found in patients who are biopsied during an episode of clinical exacerbation of their disease or other superimposed acute process.

The differential diagnosis of UIP includes other IIPs, especially fibrotic forms of NSIP. Importantly, several disorders with known etiology may present with advanced lung fibrosis, including asbestosis, collagen vascular diseases manifesting in the lung, chronic hypersensitivity pneumonitis, chronic radiation pneumonitis, and even certain genetic disorders such as Hermansky-Pudlak syndrome.1

Patients with IPF have characteristic abnormalities seen on conventional chest radiographs and HRCT scans.1–2 Peripheral reticular opacities, particularly at the lung bases, are the most common abnormality observed on chest radiographs. These opacities are commonly bilateral, somewhat asymmetric, and associated with a loss of lower lobe volume. Some patients with IPF may have normal chest radiograph findings, but evidence of disease is typically found on HRCT scans. Reticular abnormalities are commonly seen on HRCT scans, which are usually patchy, peripheral, subpleural, and bibasal in distribution. Ground-glass attenuation may be present, but it is always less extensive than the reticular abnormalities and often is confined to areas of more advanced fibrosis. In areas of severe disease, traction bronchiectasis and bronchiolectasis with subpleural honeycombing may be evident. In early stages of disease, however, the changes seen on HRCT scans may be subtle. IPF may appear as a blush of linear opacities at the bases and periphery of the lung. These consistently touch the pleura, where they form gently curving arcades surrounding darker zones of lung. Under the microscope, the zones encircled by fibrosis often contain some alveolar walls, suggesting that some of the honeycomb cysts seen on CT scans are actually lobules, the central regions of which have been attenuated by the contraction of more peripheral lobular fibrosis. Other disorders that may present with similar features on HRCT scans include asbestosis, collagen vascular disease, chronic hypersensitivity pneumonitis, and end-stage sarcoidosis.1

The pathogenesis of UIP/IPF is thought to involve multiple microscopic injuries or “hits” to the lung, which occur and recur over many years.16 These hits induce focal fibroblast proliferation with subsequent collagen deposition and ultimately the formation of dense fibrosis. The episodic and spatially separated injury events account for the temporal heterogeneity noted in the histologic pattern of UIP. Moreover, the continuing and recurrent pattern of lung injury accounts for the progressive course of IPF, which is typified by a gradual, stepwise deterioration in lung function. Superimposed on this clinical course are occasional periods of rapid decline in lung function, which are thought to be due to accelerated disease, intercurrent viral infection with the development of organizing pneumonia, or diffuse alveolar damage.1 These acute exacerbations may be mild or severe, but can lead to respiratory failure and death.

In 1994, Katzenstein and Fiorelli17 recognized that a significant percentage of patients with clinical IIP could not be readily “pigeon-holed” into one of the main groups of the original Leibow classification. She proposed the term “nonspecific interstitial pneumonia” (ie, NSIP), and postulated that it resulted from a single episode of lung injury that resulted in varying amounts of inflammation and diffuse fibrosis in the alveolar walls. In the original description by Katzenstein and Fiorelli,,17 three subgroups of NSIP were recognized on the basis of whether the histology showed chronic interstitial inflammation only (group I), a mixture of inflammation and fibrosis (group II), or predominantly interstitial fibrosis with minimal inflammation (group III). Although originally intended to identify patients with a variety of different diseases who had a nonspecific histologic pattern, the concept of NSIP has evolved, and in the ATS/ERS consensus classification of the IIPs, an idiopathic form has been given a provisional status.1 NSIP still likely represents a heterogeneous group of disorders, as patients with different clinical courses can be identified.

The histology of NSIP is temporally uniform consistent with a single episode of lung injury.1,16 When NSIP is predominantly cellular, chronic interstitial inflammation involves the alveolar walls (Fig 2
). Type II pneumocyte hyperplasia is often found in areas of inflammation. The distribution of inflammatory lesions may be variable, but, unlike UIP, little spared lung is present in biopsy specimens. At the other end of the spectrum, the fibrotic form of NSIP may include advanced fibrosis with architectural remodeling, or, in some cases, the fibrosis may show more diffuse involvement of the lung with relative preservation of the lung architecture. Unlike UIP, the fibrosis seems to be temporally homogeneous.

Several retrospective studies4–6,18 have compared the prognosis of NSIP and UIP. In these investigations, surgical lung biopsy specimens were reevaluated in a blinded manner according to current histologic definitions. In one study,4the mortality risk of patients with UIP was 17 to 24 times higher than those with NSIP (p < 0.0001). This difference persisted even after adjusting for age, gender, smoking history, and physiologic variables. In another study,5the median survival time was 2.8 years for patients with UIP but > 12 years for those with NSIP (p < 0.001). Other studies6,18 have shown that prognosis in patients with NSIP can be further refined according to histologic pattern, with the longest survival times seen in patients with a purely cellular pattern (ie, group I in the original description by Katzenstein and Fiorelli,17–). Notably, the survival time did not differ in the two NSIP groups with fibrosis, but in both cases it was longer than that for patients with UIP. In a study of 101 cases,18 the 5-year survival rates were 100% for patients with cellular NSIP, 90% for those with fibrotic NSIP, and 43% for those with UIP (p < 0.05), and the 10-year survival rates were 100%, 35%, and 15%, respectively (Fig 3
). Taken together, these studies show the following order of prognosis: cellular NSIP > fibrotic NSIP > UIP/IPF.

Transbronchial lung biopsies are very useful for diagnosing diseases that affect the central structures within the lung lobule, such as granulomatous diseases and malignant tumors, and diseases that are more diffuse in the lung by nature, such as diffuse alveolar damage, eosinophilic pneumonia, and zonal areas of alveolar proteinosis (Fig 4
). For other diseases, such as amyloidosis and lymphangioleiomyomatosis, transbronchial lung biopsy will sometimes be diagnostic, but only when the biopsy specimen encompasses the diagnostic lesion. In contrast, transbronchial biopsy is not helpful in making a diagnosis of UIP or most other IIPs, (except AIP), even though abnormal findings may be found in some cases. Transbronchial biopsies rarely sample the peripheral aspects of the lobule (ie, the primary and most diagnostic site of IPF), and specimens are typically too small for reliably evaluating the distribution of fibrosis or inflammation.2 Nonetheless, transbronchial biopsy may be helpful in excluding UIP or other IIPs by identifying an alternative diagnosis.

Surgical lung biopsy provides the best tissue specimens for distinguishing UIP from other histologic patterns of IIP, and for excluding other diagnoses that have clinical and radiologic features that mimic IPF.1–2 As noted previously, surgical lung biopsy is necessary for establishing a definitive diagnosis of UIP/IPF. It is recommended for patients who have clinical and radiologic features that are not typical for IPF and who do not have any surgical contraindications.1–2 When indicated, video-assisted thoracoscopy is preferred to open thoracotomy as it is associated with equal biopsy quality but less morbidity and shorter hospital stays.19–20

We have come far in our studies of idiopathic diffuse lung diseases. The ATS/ERS consensus classification of IIPs emphasizes an integrated clinical, radiologic, and histologic approach to these pulmonary entities, and builds on the original findings of Hamman and Rich,7the landmark classification of Liebow and colleagues,8–10 and subsequent refinements made possible by radiologic and histologic advances. The relatively recent addition of NSIP by Katzenstein and colleagues16–17 is acknowledged and has been given a provisional status. In the final analysis, the ATS/ERS classification system is based on histopathologic criteria, because these provide better separation of the clinicopathologic entities than radiologic or clinical findings in isolation. Nevertheless, a credible final diagnosis should be made only after considering the histologic pattern within the context of available clinical and radiologic information, and determining whether the condition is truly idiopathic. In current practice, fibrosing interstitial lung diseases should not be referred to as either UIP or IPF in cases in which an underlying cause is evident.

It is probable that many cases of NSIP and other IIPs were included under the IPF/UIP umbrella in the past and may have contributed to the historical variability in clinical presentation, the response to therapy, and the prognosis of IPF. Patients with IPF/UIP have a consistently worse prognosis than those with NSIP and many other IIPs. Moreover, the fibrotic pattern of NSIP yields a worse prognosis than the cellular pattern. The take-home message is that diffuse forms of lung fibrosis adversely affect survival. By distinguishing IPF from IIPs, as well as various interstitial lung diseases of known etiology, clinicians should be better able to identify optimal treatment strategies and hopefully to improve outcomes for their patients.

. American Thoracic Society, European Respiratory Society. (2002) American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.Am J Respir Crit Care Med165,277-304

References

. American Thoracic Society, European Respiratory Society. (2002) American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.Am J Respir Crit Care Med165,277-304

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